Building family traditions.

present data showing that the regulator of the A-factor cascade in Streptomyces griseus , AdpA, possesses related family members, and they determine both the sites to which AdpA binds and a consensus DNA-binding sequence. Sequence homologues and consensus DNA binding sites of regulatory proteins were first reported more than 20 years ago, so why is this new work notewor-thy? The answer is that AdpA is a member of the large and well-known AraC/XylS family. Sequence analysis of this group of interesting and important regulatory proteins has told us disappointingly little about how they function and what they sense, however, and its members have proved frustratingly difficult to study biochemically. This new work on AdpA foretells a welcome change. AraC protein of Escherichia coli was the first member of the family to be studied (Gross and Englesberg, 1959; reviewed by Schleif, 2000). Because AraC itself is poorly soluble and difficult to purify, attention was soon also turned to related family members in the hope that they would be more tractable, and it was guessed that the rhamnose operon in E. coli would turn out to be regulated by an AraC homologue. This conjecture turned out to be correct and, indeed, two proteins, RhaR and RhaS, possessing similarity to AraC regulate the operon (Tobin and Schleif, 1987). This seeded the family for further growth that, with the advent of genomics, has become explosive. The NCBI database currently lists more than 2500 homologues in the AraC/XylS family. Many of these, however, are virtually the same protein in closely related bacteria, and one reason why the family is so big is that so many genomes have been sequenced. More telling of the size of the family is that restricting the search to specific strains reveals 39 homologues in E. coli K-12, 60 in Salmonella enterica serovar Typhimurium LT2, 42 in Yersinia pestis biovar mediaevalis 91001 , 12 in the Ames strain of Bacillus anthracis and 50 in Strepto-myces avermitilis MA-4680. The DNA-binding domain of AraC comprises the C-terminal third of the protein, and it is through the amino acid sequence of this domain that AraC/XylS family members are identified. Two family members typically possess about 20% sequence identity over this region. Ordinarily, this level of homology is borderline for concluding that two proteins have similar structures and related functions but, because the domain is just over 100 amino acids long, and a number of …